Transmembrane signal defect and absence of cancer extract induced leukocyte adherence inhibition (LAI) for leukocytes from patients with advanced cancer.

Abstract

Leukocytes from patients with early cancer exhibit leukocyte adherence inhibition (LAI) when incubated with extracts of cancer of the same organ and histogenesis, whereas leukocytes from patients with advanced cancer seldom do. To understand the reason for this refractory state, tumor antigen-induced LAI and transmembrane signalling were measured in the same leukocytes. Transmembrane signalling was measured by changes in membrane potential (delta psi) by the [3H]tetraphenylphosphonium equilibration technique. When leukocytes from patients with early breast cancer were incubated with extracts of breast cancer and malignant melanoma they showed delta psi changes consisting of depolarization and hyperpolarization beginning within 0.5 min after addition of the breast cancer extract and finishing 15 min later. Moreover, they showed no delta psi changes when incubated with extracts of normal breast tissue. Leukocytes from subjects without cancer seldom showed delta psi changes. In criss-cross experiments, leukocytes from patients with melanoma only exhibited delta psi changes when incubated with the melanoma extract. There was a strong correlation between cancer extract-induced delta psi change and LAI. The delta psi change was triggered by leukotriene-like mediators from antibody-dependent monocytes. Authentic leukotrienes triggered delta psi changes in all subpopulation of leukocytes. Leukocytes from patients with advanced breast cancer when incubated with breast cancer extract did not transmit a signal or show LAI. Brief elevation of intracellular cyclic AMP restored both delta psi change and LAI induced by breast cancer extracts, indicating that reactive leukocytes are present but in a refractory state. We conclude that leukocytes from patients with advanced cancer do not react in LAI because tumor antigen does not trigger a transmembrane signal to initiate the cascade of biochemical reactions and physiological changes for LAI.